Modulation of the B cell response to dengue virus infection by Plasmodium falciparum co-infection

恶性疟原虫合并感染对 B 细胞对登革热病毒感染的反应的调节

基本信息

  • 批准号:
    10170220
  • 负责人:
  • 金额:
    $ 18.53万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-07-01 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

Project Abstract. The primary goal of this Career Development Award is the successful transition of the PI from being a mentored to an independent research scientist, studying the immunobiology of diseases of poverty affecting children, such as dengue fever and malaria. The PI and mentoring team have designed a training plan consisting of specific objectives that will provide the PI with practical experience conducting international research, specialized skill using mass cytometry for immunologic research, proficiency in managing complex data, and expertise in the development of adaptive immunity. To achieve these objectives, the team has developed a research plan to investigate the observation that many febrile Kenyan children, with PCR- confirmed dengue virus (DENV) viremia, did not develop serum anti-DENV IgG by 1 month after infection. This antibody hyporesponsiveness to infection was unexpected. Due to the high transmission of Plasmodium falciparum (Pf) malaria in the region, observations of children with simultaneous infection with both DENV and Pf (DENV/Pf co-infection), and published evidence of impaired immunity to Pf mediated by Pf, we hypothesize that during DENV/Pf co-infection, Pf-mediated B cell dysregulation steers antigen-stimulated maturation of DENV-naïve B cells toward becoming atypical memory B cells, which are less responsive to stimulation, leading to impaired development of or rapid loss of anti-DENV IgG, particularly lower avidity antibodies. Loss of lower avidity anti-DENV antibodies may affect the risk of antibody-dependent enhancement of DENV infection, which may affect manifestations of clinical disease. To investigate this hypothesis, we propose two aims that will investigate two child acute febrile illness cohorts. In Aim 1, we will investigate the clinical disease spectrum of DENV/Pf co-infected children in relation to parasitemia, viremia, and development of anti-DENV IgG. We will use PCR to detect sub-microscopic Pf parasitemia, which may influence clinical disease or anti-DENV antibody development. We will characterize the clinical disease by infection and develop an acute febrile illness severity score to assess disease severity irrespective of infectious etiology. And we will characterize, longitudinally, the post-infectious development of anti-DENV IgG. In Aim 2, we will profile the memory B cell response after acute DENV solo- or DENV/Pf co- infection. We will use mass cytometry to characterize changes in peripheral B cell populations over time, and perform whole blood stimulation experiments to probe responses of peripheral B cells to antigen exposure. Together, the data collected will answer the question of whether concurrent Pf infection impairs development of anti-DENV antibody responses in an antigen non-specific manner. The results may raise the question of whether and how Pf co-infection might affect vaccine-elicited serum antibody responses, which will provide important considerations in the planning for future deployment of DENV, and possibly other, vaccines.
项目摘要。 这一职业发展奖的主要目标是让PI成功地从 指导独立研究科学家,研究影响贫困的疾病的免疫生物学 儿童,如登革热和疟疾。PI和指导团队已经设计了培训计划 由具体目标组成,这些目标将为国际合作提供实践经验 研究,运用质量细胞术进行免疫学研究的专门技能,熟练管理复合体 在发展适应性免疫方面的数据和专业知识。为了实现这些目标,该团队已经 制定了一项研究计划来调查观察到的许多发烧的肯尼亚儿童,通过聚合酶链式反应- 确诊为登革病毒(DENV)病毒血症,感染后1个月未出现血清抗DENV-Ig G。这 抗体对感染的低反应性是出乎意料的。由于疟疾的高传播性 该地区恶性疟疾儿童同时感染DENV和DNV的观察 PF(DENV/PF混合感染),并发表了由PF介导的对PF的免疫受损的证据,我们假设 在DENV/PF混合感染过程中,PF介导的B细胞失调引导抗原刺激 DENV-幼稚B细胞向非典型记忆B细胞的成熟,后者反应较慢 易受刺激,导致抗-DENV免疫球蛋白发育受损或迅速丧失,尤其是低水平 亲和力抗体。失去低亲和力的抗DENV抗体可能会影响抗体依赖的风险 DENV感染增强,可能影响临床疾病的表现。来调查这件事 假设,我们提出了两个目的,将调查两个儿童急性发热疾病队列。在目标1中,我们将 调查DENV/PF混合感染儿童与寄生虫血症的临床疾病谱, 病毒血症和抗DENV免疫球蛋白的发展。我们将使用聚合酶链式反应来检测亚显微肺孢子虫寄生虫病, 这可能会影响临床疾病或抗DENV抗体的发展。我们将描述临床的特点 通过感染感染疾病,并制定急性发烧疾病严重程度评分,以评估疾病严重程度 传染病病原学的研究。我们将纵向描述感染后抗-DENV的发展 免疫球蛋白。在目标2中,我们将描述急性DENV单独或DENV/PF联合感染后记忆B细胞的反应。 感染。我们将使用质量细胞术来表征外周B细胞随时间的变化,以及 进行全血刺激实验,检测外周B细胞对抗原暴露的反应。 总而言之,收集的数据将回答这样一个问题:并发的PF感染是否损害了 抗DENV抗体以抗原非特异性方式反应。这一结果可能会引发一个问题: PF合并感染是否以及如何影响疫苗引起的血清抗体反应,这将提供 在规划未来部署DENV疫苗以及可能的其他疫苗时的重要考虑因素。

项目成果

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David Manh-Tung Vu其他文献

David Manh-Tung Vu的其他文献

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{{ truncateString('David Manh-Tung Vu', 18)}}的其他基金

Modulation of the B cell response to dengue virus infection by Plasmodium falciparum co-infection
恶性疟原虫合并感染对 B 细胞对登革热病毒感染的反应的调节
  • 批准号:
    10433976
  • 财政年份:
    2018
  • 资助金额:
    $ 18.53万
  • 项目类别:
Improved meningococcal vesicle vaccines
改进的脑膜炎球菌囊泡疫苗
  • 批准号:
    6772650
  • 财政年份:
    2003
  • 资助金额:
    $ 18.53万
  • 项目类别:
Improved meningococcal vesicle vaccines
改进的脑膜炎球菌囊泡疫苗
  • 批准号:
    6906648
  • 财政年份:
    2003
  • 资助金额:
    $ 18.53万
  • 项目类别:
Improved meningococcal vesicle vaccines
改进的脑膜炎球菌囊泡疫苗
  • 批准号:
    6692851
  • 财政年份:
    2003
  • 资助金额:
    $ 18.53万
  • 项目类别:

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